1. Field of the Invention
The present invention concerns novel pharmaceutically active triterpene derivatives, pharmaceutical compositions containing the same, their use as medicaments, and the use of the compounds for the manufacture of specific medicaments. The present invention also concerns a method of treatment involving administration of the compounds. Specifically, the compounds are derivatives of betulinic acid having substitutions at one or more of the C-3, C-28 and C-19 positions as further described herein.
The novel compounds are useful as antiretroviral agents. In particular, the novel compounds are useful for the treatment of Human Immunodeficiency Virus (HIV).
2. Related References
HIV is a member of the lentiviruses, a subfamily of retroviruses. HIV infects and invades cells of the immune system; it breaks down the body's immune system and renders the patient susceptible to opportunistic infections and neoplasms. The immune defect appears to be progressive and irreversible, with a high mortality rate that approaches 100% over several years.
U.S. Pat. No. 5,679,828 mentions betulinic acid and dihydrobetulinic acid derivatives, including 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (also known as (3β)-3-(carboxy-3-methyl-1-oxobutoxy)-lup-20(29)-en-28-oic acid) (structure shown below), as potent anti-HIV agents.

U.S. Pat. No. 6,642,217 mentions the use of betulin and analogs thereof for treating fungal and yeast infections.
U.S. Patent Application No. 20050239748 mentions N-methylglucamine, potassium, and sodium pharmaceutical salts of 3-O-(3′,3′-dimethylsuccinyl)betulinic acid that are useful in the treatment of HIV and related diseases.
U.S. Patent Application No. 20030186945 mentions method of preparing and use of prodrugs of betulinic acid derivatives.
WO application WO 00/46235 mentions novel betulinic acid derivatives, processes for preparing such derivatives and its use as cancer growth inhibitors.
An American Chemical Society Abstract entitled “Novel Synthetic Analogs of Betulinic Acid and their Biological Activity” by Pranab K. Gupta and Bashir Kaskar bearing a publication date of March 2002 mentions betulinic acid analogs having antitumor activity against human melanoma.
It is well known in the art that highly water soluble medicinal preparations, when administered orally, result in efficient absorption of such preparations from the gastrointestinal tract into systemic circulation. Another hallmark of such preparations is the rapid rate at which they are absorbed into the systemic circulation resulting in a high concentration of the active agent in the blood. Despite recent progress in the development of HIV therapeutic options, there remains a need for drugs having different or enhanced anti-HIV properties relative to currently marketed pharmaceuticals.
The technical problem underlying the invention relates to the need to improve certain properties of existing triterpene derivatives, such as solubility, in order to facilitate the manufacture and formulation of pharmaceuticals having improved pharmaceutical properties.
A first challenge in synthesizing the homologated triterpenes betulin, uvaol, erythrodiol and moradiol lies in the differentiation of the C-3 and C-28 hydroxyl groups.
A second challenge in synthesizing the homologated triterpenes betulin, uvaol, erythrodiol and moradiol results from the extreme steric hindrance at the C-28 position. The crowded C-28 position of betulin, uvaol, erythrodiol and moradiol interferes with many chemical reactions that might be feasible in reactions where it is desired to activate a less hindered carbon. While previous attempts to introduce heteroatoms, such as nitrogen and oxygen, have been successful, there have been no reports of synthetic processes which introduce one or more carbon atoms to the C-28 functionality. Indeed, the failure of diazomethane, generally considered to be a very reactive nucleophile, to react with the C-28 position under typical reaction conditions induced considerable skepticism amongst experts that the introduction of one or more carbon atoms to the C-28 functionality was possible. In many cases, diazomethane has been reported to add within seconds or, in some cases minutes.
A need continues to exist for novel compounds which possess potent antiretroviral activity, especially anti-HIV activity, with improved biodistribution properties and different mechanisms of action.
A further need exists for novel compounds which possess potent antiretroviral activity, especially anti-HIV activity, with superior drug-plasma protein binding properties.
A further need exists for methods of synthesizing novel compounds which possess potent antiretroviral activity, especially anti-HIV activity, with improved biodistribution properties and different modes of action.
A further need exists for methods of treating HIV-infected patients with novel compounds which possess potent antiretroviral activity, especially anti-HIV activity, with improved biodistribution properties and different modes of action.